Integrated Platform to study Neurodegeneration in Alzheimer’s Disease

Project Summary/Abstract In Alzheimer's disease (AD), the accumulation of intracellular posttranslationally modified Tau aggregates, is a hallmark of AD pathology and a strong correlate of cognitive impairment. While the dozen or so Posttranslational Modifications (PTMs) on Tau in pathological aggregates have been studied for decades, our new quantitative and qualitative mass spectrometry approaches have discovered ~100 PTMs in the angular gyrus from 98 human Alzheimer's Disease patients in these aggregates, i.e. Braak stages V/VI, and age matched control subjects without pathological changes in the frontal lobe. In this proposal, we aim to develop a large-scale proteomics platform to map the temporal occurrence of PTMs as disease progresses. We will examine a valuable new set of cases, selected to encompass all Braak stages from 0 to VI. All cases in this new cohort will have detailed premortem clinical data, which will allow us to detect and assess correlations between clinical and pathophysiological findings and any tau PTM that is identified in this study. For this analysis, we will study 3 brain regions (entorhinal/amygdala, and temporal and visual cortex) in 20 Braak 0 subjects; 40 early stage Braak I/II subjects; 40 mid stage Braak III/IV subjects; and 40 end stage Braak V/VI subjects. We will also map the global proteomes of the brain specimens from this well-characterized patient cohort to identify the enzymes associated with these Braak stage dependent PTMs. The findings of the tau characterization and mapping of the proteomes will be validated using widely accepted Tau sensor assays used to study Tau aggregation in AD. In summary, this Tau PTM specific dataset, the deep proteome maps and the subsequent validation experiments in seeding assays will be used to test our overarching hypothesis: Understanding how the progressive accumulation of Tau PTMs results in the toxicity and seeding competence of tau, and mapping the disease progression dependence of these PTMs and the enzymes responsible for them will allow us to develop interventional strategies at earlier and prodromal stages of disease.